Prostate cancer remains one of the most commonly diagnosed malignancies and the second leading cause of cancer-related death in American men. Its long latency renders prostate cancer an excellent target for chemoprevention using complementary and alternative medicines (CAMs). CAMs, such as the Indian Ayurvedic medicine constituent guggulipid (GL), provide a potential new source of readily available, cheap, and safe therapies. Our preliminary studies indicate that GL suppresses growth of human prostate cancer cells by causing apoptotic cell death in association with suppression of activating phosphorylation of Akt. The serine/threonine kinase Akt is constitutively activated in human prostate cancers, promoting cell proliferation, survival, and angiogenesis. It is also closely associated with the development of prostatic intraepithelial neoplasia and hormone-independence. The proposed studies are targeted towards determining the chemopreventive potential of GL using preclinical models of prostate cancer, as well as elucidating the mechanism of its anti-cancer effects. The chemopreventive efficacy of orally administered GL will be assessed in both a trangenic (TRAMP) mouse model genetically predisposed to developing prostate cancer, and in a xenograft nude mouse model orthotopically implanted with bioluminescent human prostate cancer cell lines (to confirm if the observed effects are relevant to human prostate cancer cells). To elucidate the mechanisms by which GL modulates Akt-associated pro-survival mechanisms, standard in vitro assays for these events will be conducted using well established androgen-dependent (LNCaP) and androgen-independent (PC-3) prostate cancer cell lines. A reduction in tumor growth and metastases following GL treatment in these in vivo models of prostate cancer will provide an obligatory impetus to explore the potential of GL to prevent prostate cancer in a clinical setting. Furthermore, the determination of the mechanisms by which GL promotes apoptosis of prostate cancer cells will facilitate: discovery of biomarkers of GL activity for use in future clinical trials, optimization of GL treatment, and development of combination regimens with GL and other mechanistically distinct drugs. [unreadable] [unreadable] [unreadable] PUBLIC HEALTH RELEVANCE: Prostate cancer remains the second leading cause of cancer-related deaths in American men. Complementary and alternative medicines, such as the Ayurvedic herbal remedy and dietary supplement guggulipid (GL), provide a potential new source of anti-cancer therapies. The proposed studies will determine if and how GL can be used to delay the onset and/or progression of prostate cancer, possibly opening a new avenue of readily available, cheap, and safe therapies to men suffering from prostate cancer. [unreadable] [unreadable] [unreadable]